Leptin protects the pancreas from damage induced by caerulein overstimulation by modulating cytokine production

Jaworek, Jolanta; Bonior, Joanna; Pierzchalski, Piotr; Tomaszewska, Romana; Stachura, Jerzy; Sendur, R; Leja, A.; Jachimczak, B.; Konturek, Peter C.; Bielański, Władysław; Pawlik, Wiesław W.; Konturek, Stanisław J.

doi:10.1159/000055897

Cited by 33 publications

(27 citation statements)

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“…In CIP rats, leptin decreases the plasma level of TNFα and increases the plasma level of IL-4, an anti-inflammatory cytokine [12]. Furthermore, Jaworek et al suggested that leptin protects the pancreas by the inhibiting of pancreatic enzyme secretion [12]. In the present study, dietary restrictions did not completely prevent pancreatitis in female WBN/Kobfatty rats.…”

Section: Discussioncontrasting

confidence: 53%

“…In caerulein-induced pancreatitis (CIP), plasma leptin levels are increased and the onset of pancreatitis is accompanied by increased pancreatic expression of the leptin gene [14]. In CIP rats, leptin decreases the plasma level of TNFα and increases the plasma level of IL-4, an anti-inflammatory cytokine [12]. Furthermore, Jaworek et al suggested that leptin protects the pancreas by the inhibiting of pancreatic enzyme secretion [12].…”

Section: Discussionmentioning

confidence: 99%

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The Influence of Dietary Restriction on the Development of Diabetes and Pancreatitis in Female WBN/Kob-Fatty Rats

et al. 2010

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Abstract:Original WBN/Kob male rats commonly develop chronic pancreatitis by the age of 3 months, while diabetes mellitus occurs at 9 months. In contrast, female rats of this strain do not show pancreatitis or diabetes. The WBN/Kob-fatty rat is a homozygous (fa/fa) congenic strain for the fa allele of the leptin receptor gene (Lepr). In WBN/Kob-fatty rats, both females and males provide a model of non-insulin-dependent diabetes with obesity. The leptin receptor fatty gene (Lepr fa ) induces obesity and hyperphagia. In the present study, we examined the effect of dietary restriction on pancreatitis and diabetes in female WBN/Kob-fatty rats. Five female fatty rats comprised a restricted feeding group with paired-feeding from 3 to 13 weeks of age, and five female lean rats comprised a control group with paired-feeding. At 13 weeks of age, two of the five female fatty rats of the control group developed diabetes mellitus, while no female fatty rats of the restricted feeding group developed diabetes mellitus. At this stage, pathological changes of the pancreas were observed in female fatty rats. All female fatty rats showed severe interlobular, intra-lobular and intra-islet fibrosis. In female fatty rats of the restricted feeding group, pathological changes of the pancreas were milder those of the free-feeding fatty group. Although dietary restriction could not completely prevent pancreatitis in female fatty rats, the development of diabetes was inhibited by its reduction of the severity of pancreatitis.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

The Influence of Dietary Restriction on the Development of Diabetes and Pancreatitis in Female WBN/Kob-Fatty Rats

et al. 2010

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“…Therefore, failure to express these anti-inflammatory proteins may contribute to severity of the response in obesity. Because leptin regulates inflammation and exerts acute protective effects in models of AP (13)(14)(15), it was important to differentiate between the direct effects of leptin deficiency and those mediated by massive obesity. Short-term leptin administration did not protect ob/ob mice from AP and actually worsened hypocalcaemia and resulted in increases in lipase, SAA, and IFN-␥ levels.…”

Section: Discussionmentioning

confidence: 99%

“…In patients with AP, a correlation between serum leptin and disease severity has been reported by some investigators but not by others (11,12). Although in animal models administration of leptin decreases AP severity (13)(14)(15)(16), more severe disease is present in leptin-deficient ob/ob and leptin receptordeficient db/db mice as well as leptin-receptor mutant fa/fa rats (17,18). However, the differential effect of obesity versus leptin deficiency has not been fully investigated.…”

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confidence: 99%

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Sennello¹,

Fayad²,

Pini³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short-and long-term leptin replacement therapy. Shortterm leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.cytokines ͉ inflammation ͉ obesity ͉ pancreas A cute pancreatitis (AP) is an inflammatory disorder that ranges from interstitial edema to confluent necrosis and hemorrhage. In severe cases, progress to circulatory shock, acute lung injury, renal failure, and eventual death may occur (1). Despite some controversy, numerous studies have demonstrated that obesity is associated with increased risk of the severe form of AP and with development of life-threatening complications (2-8). However, the mechanism by which increased adiposity worsens AP remains unknown.Leptin, a protein mainly produced by adipocytes, is a critical regulator of appetite (9). Leptin exerts important regulatory effects on inflammation (10). In the context of AP, the role of leptin remains controversial. In patients with AP, a correlation between serum leptin and disease severity has been reported by some investigators but not by others (11,12). Although in animal models administration of leptin decreases AP severity (13-16), more severe disease is present in leptin-deficient ob/ob and leptin receptordeficient db/db mice as well as leptin-receptor mutant fa/fa rats (17, 18). However, the differential effect of obesity versus leptin deficiency has not been fully investigated.IL-12 and IL-18 are two proinflammatory cytokines that drive the Th1 cell response, characterized by high levels of IFN-␥ (19). Both cytokines are mainly produced by monocytes/macrophages....

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“…In caerulein-induced pancreatitis (CIP), plasma leptin levels are increased and the onset of pancreatitis is accompanied by increased pancreatic expression of the leptin gene [12]. In CIP rats, leptin decreases the plasma level of TNF, and increases the plasma level of IL-4, an anti-inflammatory cytokine [9]. Furthermore, Jaworek et al stated that leptin protects the pancreas by inhibition of pancreatic enzyme secretion [9].…”

mentioning

confidence: 99%

Progression of Pancreatitis Prior to Diabetes Onset in WBN/Kob-Leprfa Rats

Akimoto

Terada

Shimizu

2012

The Journal of Veterinary Medical Science

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ABSTRACT. We established the WBN/Kob-Lepr fa rat as a new congenic strain for the fa allele of the leptin receptor gene (Lepr). Homozygous (fa/fa) WBN/Kob-Lepr fa rats provide a model of non-insulin-dependent diabetes, although its onset is secondary to pancreatitis. In the present study, we compared histopathological observations of pancreatitis in each genotype of this rat, to examine its suitability as a model of pancreatitis. The histopathological findings of the pancreatitis revealed intense changes dependent on age, such as hemorrhage or hemosiderin deposition. The pancreatitis in homozygous (fa/fa) WBN/Kob-Lepr fa rats were more severe than those of WBN/ Kob rats. Pancreatitis is a common disorder of the exocrine the pancreas in dogs and cats. Clinical diagnosis of chronic pancreatitis is challenging because the disease is usually mild or subclinical, and its clinical signs are often the same as those of complicating or concurrent diseases. Pancreatitis is inflammation of the pancreas introduced by autodigestion and results in leakage of digestive enzymes. In rats and mice, experimental pancreatitis can be induced by ethanol feeding, [30] Original WBN/Kob rats were the spontaneous model of the pancreatitis [22]. Male WBN/Kob rats commonly develop chronic pancreatitis by the age of 3 months, while diabetes mellitus occurs at 9 months [10,18,19,28]. In contrast to males, female rats of this strain do not show pancreatitis.The leptin receptor fatty gene (Lepr fa ) is a recessive mutation that leads to leptin receptor deficiency, and homozygous animals (fa/fa) show obesity, hyperphagia, insulin resistance, hyperinsulinemia, and glucose intolerance [5,13,27,31]. The leptin receptor fatty gene accelerates pancreatitis and diabetes in WBN/Kob-Lepr fa rats. In the present study, we compared histopathological observations of pancreatitis in each genotype, to examine the suitability of using WBN/Kob-Lepr fa rats as a model of pancreatitis. Each genotype (fa/fa, +/fa, and +/+) of WBN/Kob-Lepr fa rats was produced by mating heterozygous (+/fa) males with heterozygous (+/fa) females. Genotyping of the fa mutation was performed according to the method described by Masuyama [15]. The animals were given a commercial diet (MF, Oriental Yeast Co. Tokyo, Japan) and tap water ad libitum, and were housed in an air-conditioned room (24  2C, 50~60% relative humidity, and lights on for 14 hr per day from 6:00 to 20:00). The number of animals in each group is detailed in Table 1. At 7, 9, 11, and 13 weeks of age, a blood sample was collected for each genotype (fa/fa, +/fa, and +/+), while blood glucose levels were measured with a portable glucose meter (Asensia Breeze) (Bayer-Sankyo). Rats were then sacrificed by ether anesthesia. The pancreas was removed, fixed overnight in Bouin's solution, and embedded in paraffin for histopathological analyses. Serial 4-m sections were cut and then stained with hematoxylin-eosin for histological examination. All sections were examined histopathologically and findings were graded from norm...

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Leptin protects the pancreas from damage induced by caerulein overstimulation by modulating cytokine production

Cited by 33 publications

References 36 publications

The Influence of Dietary Restriction on the Development of Diabetes and Pancreatitis in Female WBN/Kob-Fatty Rats

The Influence of Dietary Restriction on the Development of Diabetes and Pancreatitis in Female WBN/Kob-Fatty Rats

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Progression of Pancreatitis Prior to Diabetes Onset in WBN/Kob-Leprfa Rats

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